Fatty acid derivatives

ABSTRACT

The invention relates to a novel acylate which is the reaction product of (a) a substance which is selected from the group consisting of naturally occuring alpha-aminocarboxylic acids, neurotransmitters other than such acids, and central or peripheral nervous system pharmacologically active compounds, and containing a functional group including an acylatable hydrogen atom, or a reactive derivative thereof; and (b) an essential fatty acid or a reactive derivative thereof; and including the pharmaceutically acceptable salts of such acylates possessing a basic and (or) acidic function; and to their functional derivatives. The acylates and their functional derivatives may be used for treatment of a disease or condition related to a neurotransmitter defector deficiency, or to another central or peripheral nervous system defect or deficiency, and in particular Parkinson&#39;s disease.

This application is the US national phase of international applicationPCT/IL99/00437 filed Aug. 11, 1999 which designated the U.S.

FIELD AND BACKGROUND OF THE INVENTION

The present invention relates to acylates for treatment of a disease orcondition related to a neurotransmitter defect or deficiency, or toanother central or peripheral. nervous system defect or deficiency.

As detailed, for example, in U.S. Pat. No. 4,826,877 (Stewart et al.)and U.S. Pat. No. 4,868,212 (Horrobin), the essential fatty acidsconsist of the n-3 series derived from and including α-linolenic acidand the n-6 series derived from and including linoleic acid; sinceneither α-linolenic acid nor linoleic acid are manufactured in the body,they must be provided by food. The n-3 series thus includes α-linolenic,Δ-6,9,12,15-octadecatetraenoic, Δ-8,11,14,17-eicosatetraenoic,Δ-5,8,11,14,17-eicosapentaenoic, Δ-7,10,13,16,19-docosapentaenoic andΔ-4,7,10,13,16,19-docosahexaenoic acids, and the n-6 series thusincludes linoleic, Δ-6,9,12-octadecatrienoic (γ-linolenic),Δ-8,11,14,-eicosatrienoic (dihomo-γ-linolenic),Δ-5,8,11,14-eicosatetraenoic (arachidonic),Δ-7,10,13,16-docosatetraenoic (adrenic) andΔ-4,7,10,13,16-docosapentaenoic acids. The term “essential fatty acids”in the present specification and claims means all twelve of theabove-mentioned fatty acids.

In U.S. Pat. No. 4,826,877, there is described use of the essentialfatty acids for the prevention or treatment of diabetic neuropathy andother long term complications of diabetes mellitus. In U.S. Pat. No.4,868,212, such acids are used in treatment of atopic disorders, whilein U.S. Pat. No. 5,591,446 (Melnik et al.), γ-linolenic and/ordihomo-γ-linolenic acids are used for atopy prophylaxis. In U.S. Pat.No. 4,497,827 (Nelson), arachidonic acid analogues are utilized asanti-inflammatory, antiallergenic and antibrochoconstriction agents. InU.S. Pat. No. 3,995,059 (Fukumaru), N-(α-alkyl) benzylamides of C₁₃-C₂₅aliphatic carboxylic acids are used for lowering elevated levels ofcholesterol in the blood.

In U.S. Pat. Nos. 5,599,840, 5,468,776, 5,416,114, 5,288,755, 5,120,763and 4,851,431, to Yehuda, S., there are described compositions whichcomprise a combination of α-linolenic acid and linoleic acid, within arange of strictly defined proportions, stated to be useful in enhancingmemory, producing analgesia, regulating sleep, inhibiting senilitysymptoms, and in treating Alzheimer's disease and related dementia, andepilepsy. In International Patent Application No. PCT/IL97/00366,published May 28, 1998 as WO 98/21949, the same inventor described theapplication of essentially the same combination of acids, for thetreatment of multiple sclerosis. By contrast, use of mixtures ofα-linolenic acid and linoleic acid in proportions outside of thespecified range, or (as is implicit from the U.S. patents and explicitin WO 98/21949), each acid or γ-linolenic acid taken separately, orsubstituting γ-linolenic acid for α-linolenic acid in apharmacologically active mixture with linoleic acid, did not afford anysignificant pharmacological activity.

The contents of the U.S. Patents referred to in the present application,and of WO 98/21949, are incorporated herein by reference.

To the best of the present inventor's knowledge, it has been neitherdisclosed nor suggested in the prior art, to utilize acylates derivedfrom essential fatty acids, for treatment of a disease or conditionrelated to a neurotransmitter defect or deficiency, or to anothercentral or peripheral nervous system defect or deficiency. From anotheraspect, it does not appear to have been previously disclosed orsuggested in the prior art, that essential fatty acids, by formingcovalent bonds with naturally occurring α-aminocarboxylic acids,neurotransmitters other than such acids, or central or peripheralnervous system pharmacologically active compounds, would thereby havethe ability to transport such substances, in the form of the resultantacylates, across the blood-brain barrier.

Although a vast number of drugs are known to medicine, many do notrealize their full potential because of the problem of applying them atan internal body site (such as appropriate receptors), where they wouldbe most efficacious. Another aspect of this problem is the necessity toadminister a relatively large amount of an expensive drug, in order thata very small fraction will reach the appropriate body site and exert apharmacological effect. The usual procedures for drug administration areconsequently uneconomical and also frequently produce undesiredside-effects.

It is an important object of the present invention to advance thescience of pharmacology in order to avoid so far as possible theproblems set forth in the preceding paragraph. Other objects of theinvention will appear from the description which follows.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides an acylate which is thereaction product of: (a) a substance which is selected from the groupconsisting of naturally occurring α-aminocarboxylic acids,neurotransmitters other than such acids, and central nervous systempharmacologically active compounds, and containing a functional groupincluding an acylatable hydrogen atom, or a reactive derivative thereof;and (b) an essential fatty acid or a reactive derivative thereof.

In another aspect, the invention provides use of at least one acylate asdefined in the preceding paragraph, in the manufacture of a medicamentfor treatment of a disease or condition related to a neurotransmitterdefect or deficiency, or to another central or peripheral nervous systemdefect or deficiency.

In still another aspect, the invention provides a method for treatmentof a disease or condition related to a neurotransmitter defect ordeficiency, or to another central or peripheral nervous system defect ordeficiency, wherein there is administered to a human or non-human mammalan effective amount of at least one acylate as defined in the lastparagraph but one.

In yet a further aspect, the present invention also provides apharmaceutical formulation which comprises at least one acylate of theinvention, together with at least one carrier, diluent or adjuvant.

For the avoidance of doubt, it is to be noted that the preparation ofthe acylates of the present invention involves the formation of acovalent bond or bonds between a substance defined under (a), above, andone or more molecular proportions of component (b) as defined above. Theacylates may be N-acylates, O-acylates or S-acylates, or a mixture ofmore than one of these types of acylate.

Included in the compounds of the present invention are functionalderivatives of the present acylates, and in particular of such acylateswhich contain residual amino, carboxyl and/or hydroxyl groups. Thenature and range of such functional groups will be well known to personsof the art. Presently preferred functional derivatives of acylatescontaining one or more carboxylic groups are esters thereof withalcohols containing 1-4 carbon atoms. The functional derivatives appearto have similar biological activity to the non-functionalized acylates.

While the scope of the present invention is deemed not to be restrictedby any theory, it is nevertheless presently believed that enzymesassociated with relevant receptors will split the covalent bond betweenmoieties (a) and (b), whereby component (a) exhibits its pharmacologicalactivity at the site in question while the essential fattyacid—component (b)—is absorbed in the neuronal membrane.

DETAILED DESCRIPTION OF THE INVENTION

The acylates of the present invention, which by way of non-limitingexemplification may result from acylation with formation of a —CO—O—,—CO—S— or —CO—NR¹R² moiety (where each of R¹ and R² is independentlyselected from a hydrogen atom or an optionally substituted hydrocarbylgroup and NR¹R² may also constitute a heterocyclic ring), may beprepared by any of the appropriate methods known to the organic chemist,and thus the manner of their preparation does not constitute, per se, apart of the present invention. Where, in the standard methods ofreaction for preparing e.g., the amides, esters or thioesters which maybe acylates according to the present invention, reactant (a) contains anatom or substituent which interferes with such reaction, then suchinterfering atom or substituent may be blocked or protected in a mannerknown to persons in the art.

Although the present acylates will frequently be pro-drugs, that is,substances which when administered in the animal or human body releaseat the desired site a pharmacologically active entity, nevertheless,this in the alternative or additionally, the acylates may havepharmacological activity in their own right. Further, the acylatesinclude substances in which component (a) is not itselfpharmacologically active at the target site, but when releasedmetabolizes to a substance having desired pharmacological activity.

Group (a) substances include naturally occurring (x-aminocarboxylicacids, which are of course “building blocks” in the formation ofproteins which perform important functions in the animal and human body,and at least some of which acids functional also as neurotransmitters.Exemplary amino acids are α-aminocarboxylic acids and are selected fromalanine, arginine, asparagine, aspartic acid, β-carboxyaspartic acid,γ-carboxyglutamic acid, cysteine, cystine, glutamine, glutamic acid,glycine, histidine, homoserine, hydroxylysine, hydroxyproline,isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine,threonine, tryptophan, tyrosine and valine.

Two amino acids of particular importance, tyrosine and tryptophan, arenot formed in the body but must be ingested in food. Tyrosine ismetabolized successively to dopa, dopamine, norepinephrine andepinephrine (Scheme A, below), while tryptophan is metabolized first to5-hydroxytryptophan and thus to 5-hydroxytryptamine (Scheme B, below).

Group (a) substances further include other neurotransmitters, e.g.,γ-aminobutyric acid (GABA), Dopamine, Epinephrine, Norepinephrine and5-hydroxytryptamine. It will be apparent that the amino acids tyrosineand tryptophan thus perform, in the present context, the invaluablefunction of forming neurotransmitters in the body.

While Parkinson's Disease is related to a deficiency of the centralneurotransmitter dopamine, this cannot be administered to patientsbecause is cannot pass the blood-brain barrier. The conventionalsolution to this problem is the administration of Levodopa; however,this always causes undesirable side-effects, to a greater or lesserextent. Thus, in accordance with an embodiment of the present invention,there is provided a method for the treatment of Parkinson's Diseasewhich comprises treating a patient with an effective amount of at leastone compound selected from N- and/or O-acylated derivatives of tyrosine,levodopa and dopamine, where the acyl group is that of an essentialfatty acid, such as, e.g., α- or γ-linolenoyl, linoleoyl orarachidonoyl.

Such derivatives constitute presently preferred acylates of theinvention, as do also the N- and/or O-acylated derivatives ofepinephrine and norepinephrine; the N-acylated derivatives oftryptophan; and the N- and/or O-acylated derivatives of5-hydroxytryptophan and 5-hydroxytryptamine, in all of which the acylgroup is that of an essential fatty acid, such as, e.g., α- orγ-linolenoyl, linoleoyl or arachidonoyl.

It is believed to be a clear implication from the specific example setforth herein, that the acylates of the present invention (in relation tocentral neurotransmitters and the treatment of CNS-related conditionsgenerally) are able to pass the blood-brain barrier, and it may bepredicted with a reasonable degree of confidence that they would havethe ability also to access appropriate receptors in relation toperipheral nervous system conditions.

By definition, substance (a) must contain a functional group includingan acylatable hydrogen atom, or a reactive derivative thereof, in orderthat it may potentially be reacted with an essential fatty acid (or areactive derivative thereof), so as to result in formation of a prodrugaccording to the present invention. The Table which follows shows, byway of non-limiting illustration only, substances (a), classifiedaccording to their pharmacological activity, and indicating the natureof the functional group (rather than the category of compound)containing the hydrogen atom substitutable by e.g., α- or γ-linolenoyl,linoleoyl or arachidonoyl.

TABLE 1 pharmacological activity substance functional group(s)cholinomimetic Metoclopramide aromatic NH₂ anticholinesteraseEdrophonium aromatic OH antimuscarinic Cyclopentolate tertiary OHTropicamide primary OH sympathomimetic Epinephrine {phenolic + sec. OH{(aliphatic) NHCH₃ Dopamine {phenolic OH {(aliphatic)NH₂ α-adrenergicblocker Phentolamine {phenolic OH {ring NH β-adrenergic blockerPropranolol {secondary OH {(aliphatic)NHisoPr adrenergic inhibitorGuanethidine amidine ganglionic stimulator Lobeline secondary OHganglionic blocker Mecamylamine secondary OH neuromuscular blockerd-Tubocurarine phenolic OH general anesthetic Lorazepam {secondary OH{ring NH local anesthetic Procaine aromatic NH₂ hypnotic } Nitrazepamring NH antiepileptic } sedative-hypnotic Ethchlorvynol tertiary OHpsychiatric Haloperidol tertiary OH Desipramine aliphatic NHanti-Parkinson Levodopa {phenolic OH {(aliphatic)NH₂ anti-spasticBaclofen (aliphatic)NH₂ opioid analgesic Morphine {phenolic + sec. OHopioid antagonist Naloxone phenolic OH CNS stimulant Methylphenidatering NH neurotransmitter α-aminocarboxylic acids* }(aliphalic) NH₂γ-aminobutyric acid (GABA) } Dopamine (see above) Epinephrine (seeabove) Norepinephrine {phenolic + sec. OH {(aliphatic) NH₂5-hydroxytryptamine {phenolic OH (seratonine) {(aliphatic) NH₂*α-aminocarboxylic acids may contain also OH or SH functions, which maybe acylated additionally or alternatively

The acylates of the invention may be formulated with carriers, diluentsand adjuvants as is well known in the pharmaceutical art and they may beadministered in the usual modes, such as orally, parenterally, rectallyof transdermally. Consequently, the present pharmaceutical formulations,except insofar as they contain the present novel and inventive acylates,are not otherwise to be regarded as innovative per se, and they may bemanufactured and administered by known methods.

The invention will now be illustrated by the following Examples.

EXAMPLE 1 N-α-linolenyltvrosine

Similarly to the method described by Inman, J. K. et al., EnzymeStructure, 1983, vol. 91 p. 564, Academic Press, acetonitrile (0.25 ml)and methanol (1 ml) were dissolved in ether (5 ml). In presence ofanhydrous calcium sulfate, and in a nitrogen atmosphere, the solution,kept at 0° C., was saturated with anhydrous HCI, and thereaftermaintained at 0° C. for two hours. The solution was shaken with dryether (50 ml) and after standing a further hour at 0° C., the productcrystallized out and was collected by decantation and washing with 2-10ml cold dry ether. It was dried under vacuum and stored for 24 hoursprior to use in a tightly stoppered bottle under anhydrous conditions at−20° C.

The initially formed methylacetamidate hydrochloride was reacted inknown manner with tyrosine (1 g) and α-linolenic acid (1 ml), and thedesired N-(α-linolenoyl)tyrosine was isolated. The identity of theproduct as N-(α-linolenoyl)tyrosine was confirmed by testing in a massspectrometer (VG70) which showed the presence of N-(α-linolenoyl) andtyrosine moieties, as well as by use of a plane-polarized infraredspectrophotometer (Varian IR 427) which inter alia showed the presenceof the amide group.

In an alternative method, the carboxylic acid function in tyrosine isprotected prior to reaction with α-linolenic acid (or a reactivederivative thereof), and the resultant carboxyl-protectedN-(α-linolenoyl)tyrosine is deprotected, giving the desired product.

BIOLOGICAL TESTING OF N-β-LINOLENYLTYROSINE (I)

Rotational Behavior

One of the major behavioral methods to measure the increase in dopamineactivity in the brain is rotational behavior. Dopamine is theneurotransmitter in the striatum. The striatum controls motor movementsand motor integration. In the brain there are two striata, in the rightand left hemispheres, respectively. Unilateral ablation of a striatumwill result in walking in circles, as the intact striatum is stillfunctioning; Ungerstadt, U. et al., Brain Res., 1970, 24: 485-492,created a lesion in one striatum and measured the effect on rotationalbehavior. Since then, this technique has been used to screen molecules,such as stimulants or potential anti-Parkinson drugs, which induceincrease in dopaminergic activity.

Experimental Animals

Groups of 6 male Sprague-Dawley rats (Charles River Laboratories,Wilmington, Mass.) weighing 100-120 g, were housed 6 per cage in awell-ventilated and air-conditioned room of ambient temperature (22±2°C.) and relative humidity 45%. The rats had access to food (Big RedLaboratory Chow, Agway Inc., Syracuse, N.Y.) and water ad libitum. Light(“Vita Light”, Duro Test Corp., North Bergen, N.J.) was provided between9 am and 9 pm.

Lesions

All surgery was performed under anesthesia (sodium pentobarbital, 50mg/ml, as required). The rats were placed in a Kopf stereotaxicinstrument (model #900). Unilateral anodal electrolytic lesions weremade with constant current supply (lesion-producing device #58040,Stoelting, Chicago, Ill.). Current (2.0 mV for 10 seconds) was passedthrough stainless steel insulated wire pe 32, 0.008 inches diameter(“Formax”, Stoelting, Chicago, Ill.), bared only at the tip. Thecoordinates (modified from Konig and Klippel, 1963) for caudate nucleuslesion were: A 8.5, L 2.2, V+1.8. The lesions were made in the left sideof the brain. Tests were made at day 4 after surgery.

Rotational Behavior

Rotational behavior was tested in a rotameter, modified from the designof Ungerstedt et al., 1970. Each rat, mounted in a special harness, wasplaced in an acrylic transparent dome of 41 cm radius. Its rotationalmovements were transduced from the harness via a stainless steel tube (⅛inch) and a precision universal joint (Pic BC 12) to a 5K linearpotentiometer (Spoctrol), which received an excitation current from aSanborn Polygraph (7702 B recorder, Hewlett-Packard). The potentiometer(preamplifier 8805 A) measured and recorded the changes in the amount ofcurrent which passed through it, resulting from the rotational movementsof the rats. When each rat turned to the right, the recording pen wasdeflected upward; a leftward turn deflected the pen downward. Continuousrecordings were made on chart paper RJN at a speed of 1 mm/sec.

Procedure

Each rat was placed in the rotameter and treated with an i.p. injectionof saline or (I) (10 mg/kg) as prepared above. Two observers watched therats for abnormal behavior (i.e. stereotype—which was not found). Thefrequency of turning was measured between 30-40 minutes post-injection.After this time lapse, the treated rats had increased their rate ofrotational motion from 4 cycles/minute to 40 cycles/minute.

At the end of the experiment, the rats were removed from the rotameterand the brain was taken for verification of the lesion as follows. Therats were given an overdose of pentobarbital and perfused with saline,followed by 10% formalin. Brains were removed and serial coronal sliceswere made at 40 microns using a freezing microtome. Representativeslices were stained with Cresyl Violet and mounted on slides. Thehistological examination showed that in all tested rats the lesion wasconfined to the striatum. All other brain areas were intact.

EXAMPLE 2 N-β-linolenyltyrosine Methyl Ester

This functional derivative of N-β-linolenyltyrosine was prepared asfollows. To an ice-cooled solution of p-tert-butoxy-β-phenylalaninemethyl ester, HCl salt (2.1 g) in CH₂Cl₂ (50 ml), in an argonatmosphere, was added dropwise Et₃N (1 ml=0.74 g), and then—after threeminutes-β-linolenic acid (1.8 g) in CH₂Cl₂ (35 ml), followed by (assolids) dicyclohexylcarbodiimide (1.5 g) and hydroxybenzotriazole (0.96g), and then DMF (35 ml), the temperature being maintained at 0° C. fortwo hours, with stirring, and finally at room temperature for 40 hours.Ethyl acetate (50 ml) was added, and the mixture was filtered,concentrated in vacuo, and again filtered. Ether (30 ml was added andthe mixture was extracted successively with water, 1% aq. HCl, 1% aq.KOH and water. The organic phase was dried (MgSO₄) and after filtrationand evaporation, a mixture of trifluoroacetic acid (70 ml) andtriethylsilane (1 ml) were added to the residue at −10° C. (argonatmosphere). The mixture was stirred for 20 minutes at 0° C., afterwhich it was allowed to attain ambient temperature, stirred for 5minutes, evaporated in vacuo at 30° C., re-evaporated with methanol(4×50 ml), and finally chromatographed on a Merck silica column (h=30cm, d=3.2 cm). Elution was effected with CHCl₃ (1.5 l), UV detection at270 nm, the product being obtained as a viscous oil (2 g), elementalcomposition confirmed by mass spectrum as C₂₈H₄₁NO₄.

High resolution mass-spectrum (Cl by CH₄): 456.310112 (M+, 100%),C₂₈H₄₂NO₄ calc. 456.311384. ¹H—NMR (CDCL₃): 0.97 (t, J=7.5 Hz; 3H), 1.28(broadened; 10H), 1.58 (m; 2H), 2.07 (m; 4H), 2.19 (t, J=5.6 Hz; 2H),2.80 (m; 2H), 3.03 (m; 2H), 3.37 (s; 3H), 4.87 (m; 1H), 5.37 (m; 6H),6.04 (d, J=8.0 Hz; 1H), 6.10 (broadened; 1H), 6.83 (m, 4H) ppm. ¹³C—NMR(CDCl₃): 14.24; 20.51; 25.49; 25.52; 25.57; 27.16; 29.08; 29.15; 29.54;36.48; 37.18; 52.40; 53.17; 115.53;126.94; 127.07; 127.70; 128.21;128.27; 130.21; 131.93; 155.45; 172.30; 173.53 ppm.

BIOLOGICAL TESTING OF N-α-LINOLENYLTYROSINE. METHYL ESTER (II)

Experimental Animals

Three groups of 12 male Sprague-Dawley rats (Charles River Laboratories,Wilmington, Mass.) weighing 100-150 g, were housed 6 per cage in awell-ventilated and air-conditioned room of ambient temperature (22±2°C.) and relative humidity 45%. The rats had access to food (Big RedLaboratory Chow, Agway Inc., Syracuse, N.Y.) and water ad libitum. Light(“Vita Light”, Duro Test Corp., North Bergen, N.J.) was provided between9 am and 9 pm. These groups were used for rotational study, the dosageof (II) being 100 mg/kg, i.p.

Rotational Behavior

1. Lesions

One group served as a control group (no treatment), a second group was asham operated group, and a third group was the operated group. Allsurgery was performed under anesthesia (sodium pentobarbital, 50 mg/ml,as required). The rats were placed in a Kopf stereotaxic instrument(model #900). Unilateral anodal electrolytic lesions were made withconstant current supply (lesion-producing device #58040, Stoelting,Chicago, Ill.). Current (2.0 mV for 10 seconds) was passed throughstainless steel insulated wire pc 32, 0.008 inches diameter (“Formax”,Stoelting, Chicago, Ill.), bared only at the tip. The coordinates(modified from Konig and Klippel, 1963) for caudate nucleus lesion were:A 8.5, L 2.2, V+1.8. The lesions were made in the left side of thebrain. Sham operated animals were treated as lesioned animals, i.e. theywere placed in the stereotaxic instrument and an electrode was placed inthe brain, but without passing electric current therethrough. Aftersurgery, each rat was placed in an individual cage. Tests were made atday 10 after surgery. At the end of the experiment, each rat was givenan overdose of pentobarbital and perfused with saline, followed by 10%formalin. Brains were removed and serial coronal slices were made at 40micra, using a freezing microtome. Representative slides were stainedwith Cresyl Violet for verification of the lesion.

2. Procedure

Details of the procedure with regard to determination of rotationalbehavior were substantially as described above for testing (I).

3. Results

Results are summarized in the following Table, which demonstrates thatadministration of (II) influences rotational behavior in a statisticallysignificant manner (ANOVA p≦0.001).

No. of rats Group in group L R L + R % L % R Control + 10 12  8  20 6040 vehicle sham + vehicle 12  7 21  28 25 75 lesion + vehicle 11  3 27 30 10 90 lesion + (II) 11 98  2 100 98  2

Blephrospasm

This is an involuntary spasm of the orbicular muscles of the eye,causing forceful closure of the eyes. Symptomatically there is asignificant increase in the rate of eyelid closures/min. This phenomenonis regarded as a type of dystonia, a decrease in the brain dopaminelevel being the etiology of this syndrome. Ro4-1284 is a powerfuldopamine-depleting agent. In saline-treated animals, Ro4-1284 is able toinduce an animal model of benign essential blephrospasm. Groups of ratssimilar to those described above were treated daily for 14 days with 25mg/kg (II), i.p., and then were challenged with a dose of 40 mg/kgRo4-1284, i.p. The results of this test were shown in the followingTable.

Group No. of rats in group rate of eyelid blinking/min.* Control 12 5.16± 1.58 Ro4-1284 12 19.08 ± 3.4  (II) followed 12 5.00 ± 1.95 by Ro4-1284(p < 0.001) *30 minutes after treatment with Ro4-1284

Conclusions of Biological testing (I) and (II) cross the blood-brainbarrier and are enzymatically converted to one or more of dopamine,norepinephrine and epinephrine. To the best of the inventor's knowledge,it has never been recorded that either α-linolenic acid or tyrosineinfluence rotational motion or blephrospasm as was found in theseexperiments. By implication, the acylates of the present inventiongenerally, including their functional derivatives, should be capable ofcrossing the blood-brain barrier and/or accessing the relevantreceptors.

While the present invention has been particularly described withreference to certain embodiments, it will be apparent to those skilledin the art that many modifications and variations may be made. Theinvention is accordingly not to be construed as limited in any way bysuch embodiments, rather its concept is to be understood according tothe spirit and scope of the claims which follow.

What is claimed is:
 1. Method for treatment of a disease or conditionrelated to a neurotransmitter defect or deficiency, or to anothercentral or peripheral nervous sysem defect or deficiency, wherein thereis administered to a human or non-human mammal an effective amount of atleast one acylate which is the reaction product of (a) a substance whichis selected from the group consisting of naturally occurringα-aminocarboxylic acids, neurotransmitters other than such acids, andcentral or peripheral nervous system pharmacologically active compounds,and containing a functional group including an acylatable hydrogen atom,or a reactive derivative thereof; and (b) an essential fatty acid or areactive derivative thereof, and including the pharmaceuticallyacceptable salts of such acylates possessing a basic and(or) acidicfunction, or of a functional derivative of said acylate including thepharmaceutically acceptable salts of such functional derivativepossessing a basic and(or) acidic function; provided that component (b)excludes Δ-4,7,10,13,16,19-docosahexaenoic acid or a reactive derivativethereof.
 2. Method according to claim 1, for the treatment ofParkinson's Disease, which comprises treating a patient with aneffective amount of at least one compound selected from N- and/orO-acylated derivatives of tyrosine, levodopa and dopamine, where theacyl group is α- or γ-linolenoyl, linoleoyl or arachidonoyl.
 3. Methodaccording to claim 1, wherein said reaction resulted in the formation ofa —CO—O— moiety; a —CO—S— moiety; or a moiety of formula —CO—NR¹R² whereeach of R¹ and R² is independently selected from a hydrogen atom or anoptionally substituted hydrocarbyl group and NR¹R² may also constitute aheterocyclic ring.
 4. Method according to claim 1, wherein saidpharmacologically active compounds are selected from amongcholinomimetics, anticholinesterase agents, antimuscarinic drugs,sympathomimetic amines, adrenergic blockers and inhibitors, ganglionicstimulators and blockers, neuromuscular blockers, general and localanesthetics, hypnotics, sedatives, psychiatric drugs, antiepileptics,anti-Parkinsonism drugs, anti-spasticity drugs, opioid analgesics andantagonists and central nervous system stimulants.
 5. Method accordingto claim 1, wherein said naturally occurring α-aminocarboxylic acids areselected from alanine, arginine, asparagine, aspartic acid,β-carboxyaspartic acid, γ-carboxyglutamic acid, cysteine, cystine,glutamine, glutamic acid, glycine, histidine, homoserine, hydroxylysine,hydroxyproline, isoleucine, leucine, lysine, methionine, phenylalanine,proline, serine, threonine, tryptophan, tyrosine and valine.
 6. Methodaccording to claim 1, wherein said other neurotransmitters are selectedfrom γ-aminobutyric acid (GABA), dopamine, epinephrine, norepinephrineand 5-hydroxytryptamine.
 7. Method according to claim 1, wherein said atleast one acylate comprises an N-acylated drivative of tryptophan; or anN- and/or O-acylated derivative of tyrosine, where the acyl group is α-or γ-linolenoyl, linoleoyl or arachidonoyl.
 8. Method according to claim1, wherein said at least one acylate comprises an N- and/or O-acylatedderivative of dopamine, epinephrine, norepinephrine or5-hydroxytryptamine, where the acyl group is α- or γ-linolenoyl,linoleoyl or arachidonoyl.
 9. Method according to claim 1, wherein saidat least one acylate comprises an N- and/or O-acylated derivative oflevodopa or 5-hydroxytryptophan, where the acyl group is α- orγ-linolenoyl, linoleoyl or arachidonoyl.
 10. An acylate which is thereaction produce of (a) a substance which is selected from the groupconsisting of neurotransmitters other than naturally occurringα-aminocarboxylic acids, and central or peripheral nervous systempharmacologically active compounds, and containing a functional groupincluding an acylatable hydrogen atom, or a reactive derivative thereof,and (b) an essential fatty acid or a reactive derivative thereof; andincluding the pharmaceutically acceptable salts of such acylatespossessing a basic and(or) acidic function; and a functional derivativeof said acylate including the pharmaceutically acceptable salts of suchfunctional derivative possessing a basic and(or) acidic function;provided that component (b) excludes Δ-4, 7, 10, 13, 16,19-docosahexaenoic acid or a reactive derivative thereof, and thatcomponent (a) is not dopamine or a reactive derivative thereof, whensimultaneously component (b) is either linoleic acid or a reactivederivative thereof or is linolenic acid or a reactive derivativethereof.
 11. Acylate according to claim 1, wherein said reaction resultsin the formation of a —CO—O— moiety; a —CO—S— moiety; or a moiety offormula —CO—NR¹R², where each of R¹ and R² is independently selectedfrom a hydrogen atom or an optionally substituted hydrocarbyl group andNR¹R₂ may also constitute a heterocyclic ring.
 12. Acylate according toclaim 10, wherein said pharmacologically active compounds are selectedfrom among cholinomimetics, anticholinesterase agents, antimuscarinicdrugs, sympathomimetic amines, adrenergic blockers and inhibitors,ganglionic stimulators and blockers, neuromuscular blockers; general andlocal anesthetics, hypnotics, sedatives, psychiatric drugs,antiepileptics, anti-Parkinsonism drugs, anti-spasticity drugs, opioidanalgesics and antagonists and central nervous system stimulants. 13.Acylate according to claim 10, wherein said other neurotransmitters areselected from γ-aminobutyric acid (GABA), dopamine, epinephrine,norepinephrine and 5-hydorxytryptamine.
 14. Acylate according to claim10, which is an N-acylated derivative of tryptophan; or an N- and/orO-acylated derivative of tyrosine, where the acyl group is α- orγ-linolenoyl, linoleoyl or arachidonoyl.
 15. Acylate according to claim10, which is an N- and/or O-acylated derivative of dopamine,epinephrine, norepinephrine or 5-hydroxytryptamine, where the acyl groupis α- or γ-linolenoyl, linoleoyl or arachidonoyl.
 16. Acylate accordingto claim 10, which is an N- and/or O-acylated derivative of levodopa or5-hydroxytryptophan, where the acyl group is α- or γ-linolenoyl,linoleoyl or arachidonoyl.
 17. A pharmaceutical formulation whichcomprises at least one acylate as defined in claim 10, together with atleast one carrier, diluent or adjuvant.